Measles is an airborne disease which spreads easily through the coughs and sneezes of infected people.[6] It may also be spread through contact with saliva or nasal secretions.[6] Nine out of ten people who are not immune and share living space with an infected person will be infected.[5] People are infectious to others from four days before to four days after the start of the rash.[5] Most people do not get the disease more than once.[6] Testing for the measles virus in suspected cases is important for public health efforts.[5]

The measles vaccine is effective at preventing the disease, and is often delivered in combination with other vaccines.[6]Vaccination resulted in a 75% decrease in deaths from measles between 2000 and 2013, with about 85% of children worldwide being currently vaccinated.[6] Once a person has become infected, no specific treatment is available,[6] but supportive care may improve outcomes.[6] This may include oral rehydration solution (slightly sweet and salty fluids), healthy food, and medications to control the fever.[6][7]Antibiotics may be used if a secondary bacterial infection such as bacterial pneumonia occurs.[6]Vitamin A supplementation is also recommended in the developing world.[6]

Measles affects about 20 million people a year,[3] primarily in the developing areas of Africa and Asia.[6] It is one of the leading vaccine-preventable disease causes of death.[11][12] In 1980, 2.6 million people died of it,[6] and in 1990, 545,000 died; by 2014, global vaccination programs had reduced the number of deaths from measles to 73,000.[8][13] Rates of disease and deaths, however, increased in 2017 due to a decrease in immunization.[14] The risk of death among those infected is about 0.2%,[5] but may be up to 10% in people with malnutrition.[6] Most of those who die from the infection are less than five years old.[6] Measles is not believed to affect other animals.[6]

Signs and symptoms

Symptoms typically begin 10–14 days after exposure.[15][16] The classic symptoms include a four-day fever (the 4 D's) and the three C's—cough, coryza (head cold, fever, sneezing), and conjunctivitis (red eyes)—along with fever and rashes.[17] Fever is common and typically lasts for about one week; the fever seen with measles is often as high as 40 °C (104 °F).[18]

Koplik's spots seen inside the mouth are diagnostic for measles, but are temporary and therefore rarely seen.[17] Koplik spots are small white spots that are commonly seen on the inside of the cheeks opposite the molars.[16] Recognizing these spots before a person reaches their maximum infectiousness can help reduce the spread of the disease.[19]

The characteristic measles rash is classically described as a generalized redmaculopapular rash that begins several days after the fever starts. It starts on the back of the ears and, after a few hours, spreads to the head and neck before spreading to cover most of the body, often causing itching. The measles rash appears two to four days after the initial symptoms and lasts for up to eight days. The rash is said to "stain", changing color from red to dark brown, before disappearing.[20] Overall, measles usually resolves after about three weeks.[18]

The death rate in the 1920s was around 30% for measles pneumonia.[28] People who are at high risk for complications are infants and children aged less than 5 years[29]; adults aged over 20 years[29]; pregnant women[29]; people with compromised immune systems, such as from leukemia, HIV infection or innate immunodeficiency;[29][30] and those who are malnourished[29] or have vitamin A deficiency.[29][31] Complications are usually more severe in adults who catch the virus.[32] Between 1987 and 2000, the case fatality rate across the United States was 3 measles-attributable deaths per 1000 cases, or 0.3%.[33] In underdeveloped nations with high rates of malnutrition and poor healthcare, fatality rates have been as high as 28%.[33] In immunocompromised persons (e.g., people with AIDS) the fatality rate is approximately 30%.[34]

Even in previously healthy children, measles can cause serious illness requiring hospitalization.[30] One out of every 1,000 measles cases progresses to acute encephalitis, which often results in permanent brain damage.[30] One or two out of every 1,000 children who become infected with measles will die from respiratory and neurological complications.[30]

The virus is highly contagious and is spread by coughing and sneezing via close personal contact or direct contact with secretions.[36] It can live for up to two hours in that airspace or nearby surfaces.[15][36] Measles is so contagious that if one person has it, 90% of nearby non-immune people will also become infected.[15] Humans are the only natural hosts of the virus, and no other animal reservoirs are known to exist.[15]

Pathophysiology

Drawing of the measles virus attaching to a skin cell

Once the measles virus gets onto the mucosa, it infects the epithelial cells in the trachea or bronchi.[40][41] Measles virus uses a protein on its surface called hemagglutinin (H protein), to bind to a target receptor on the host cell, which could be CD46, which is expressed on all nucleated human cells, CD150, aka signaling lymphocyte activation molecule or SLAM, which is found on immune cells like B or T cells, and antigen-presenting cells, or nectin-4, a cellular adhesion molecule.[40][42] Once bound, the fusion, or F protein helps the virus fuse with the membrane and ultimately get inside the cell.[40] The virus is a single-stranded negative-sense RNA virus meaning it first has to be transcribed by RNA polymerase into a positive-sense mRNA strand.[40]

After that it is ready to be translated into viral proteins, wrapped in the cell’s lipid envelope, and sent out of the cell as a newly made virus.[43] Within days, the measles virus spreads through local tissue and is picked up by dendritic cells and alveolar macrophages, and carried from that local tissue in the lungs to the local lymph nodes.[40][41] From there it continues to spread, eventually getting into the blood and spreading to more lung tissue, as well as other organs like the intestines and the brain.[15][40]

Diagnosis

Clinical diagnosis of measles requires a history of fever of at least three days, with at least one the following symptoms: cough, coryza, or conjunctivitis. Observation of Koplik's spots is also diagnostic.[19] Laboratory confirmation is however strongly recommended.[44]

Laboratory testing

Laboratory diagnosis of measles can be done with confirmation of positive measles IgM antibodies or isolation of measles virus RNA from respiratory specimens.[45] For people unable to have their blood drawn, saliva can be collected for salivary measles-specific IgA testing.[46] Positive contact with other people known to have measles adds evidence to the diagnosis. Any contact with an infected person, including semen through sex, saliva, or mucus, can cause infection.[citation needed]

Prevention

Mothers who are immune to measles pass antibodies to their children while they are still in the womb, especially if the mother acquired immunity through infection rather than vaccination.[15][39] Such antibodies will usually give newborn infants some immunity against measles, but these antibodies are gradually lost over the course of the first nine months of life.[16][39] Infants under one year of age whose maternal anti-measles antibodies have disappeared become susceptible to infection with the measles virus.[39]

In developed countries, it is recommended that children be immunized against measles at 12 months, generally as part of a three-part MMR vaccine (measles, mumps, and rubella). The vaccine is generally not given before this age because such infants respond inadequately to the vaccine due to an immature immune system.[39] A second dose of the vaccine is usually given to children between the ages of four and five, to increase rates of immunity. Vaccination rates have been high enough to make measles relatively uncommon. Adverse reactions to vaccination are rare, with fever and pain at the injection site being the most common. Life-threatening adverse reactions occur in less than one per million vaccinations (<0.0001%).[47]

In developing countries where measles is common, the World Health Organization recommend two doses of vaccine be given, at six and nine months of age. The vaccine should be given whether the child is HIV-infected or not.[48] The vaccine is less effective in HIV-infected infants than in the general population, but early treatment with antiretroviral drugs can increase its effectiveness.[49] Measles vaccination programs are often used to deliver other child health interventions as well, such as bed nets to protect against malaria, antiparasite medicine and vitamin A supplements, and so contribute to the reduction of child deaths from other causes.[50]

The Advisory Committee on Immunization Practices (ACIP) has long recommended that all adult international travelers who do not have positive evidence of previous measles immunity receive two doses of MMR vaccine before traveling.[51] Despite this, a retrospective study of pre-travel consultations with prospective travelers at United States Centers for Disease Control and Prevention (CDC)-associated travel clinics found that of the 16% of adult travelers who were considered eligible for vaccination, only 47% underwent vaccination during the consultation; of these, patient refusal accounted for nearly half (48%), followed by healthcare provider decisions (28%) and barriers in the health system (24%).[52]

Treatment

There is no specific antiviral treatment if measles develops.[36] Instead the medications are generally aimed at treating superinfections, maintaining good hydration with adequate fluids, and pain relief.[36] Some groups, like young children and the severely malnourished, are also given vitamin A, which act as an immunomodulator that boosts the antibody responses to measles and decreases the risk of serious complications.[36][53]

The use of vitamin A during treatment is recommended to decrease the risk of blindness;[60] however, it does not prevent or cure the disease.[61] A systematic review of trials into its use found no reduction in overall mortality, but it did reduce mortality in children aged under two years.[62] It is unclear if zinc supplementation in children with measles affects outcomes as it has not been sufficiently studied.[63]

Prognosis

Most people survive measles, though in some cases, complications may occur. Possible consequences of measles virus infection include bronchitis, sensorineural hearing loss,[35] and—in about 1 in 10,000 to 1 in 300,000 cases[65]—panencephalitis, which is usually fatal.[66] Acute measles encephalitis is another serious risk of measles virus infection. It typically occurs two days to one week after the measles rash breaks out and begins with very high fever, severe headache, convulsions and altered mentation. A person with measles encephalitis may become comatose, and death or brain injury may occur.[67]

Measles is extremely infectious and its continued circulation in a community depends on the generation of susceptible hosts by birth of children. In communities that generate insufficient new hosts the disease will die out. This concept was first recognized in measles by Bartlett in 1957, who referred to the minimum number supporting measles as the critical community size (CCS).[68] Analysis of outbreaks in island communities suggested that the CCS for measles is around 250,000.[69] To achieve herd immunity, more than 95% of the community must be vaccinated due to the ease with which measles is transmitted from person to person.[18] The disease was eliminated from the Americas in 2016.[70]

In 2011, the WHO estimated that 158,000 deaths were caused by measles. This is down from 630,000 deaths in 1990.[71] As of 2018, measles remains a leading cause of vaccine-preventable deaths in the world.[11][72] In developed countries, death occurs in one to two cases out of every 1,000 (0.1–0.2%).[73] In populations with high levels of malnutrition and a lack of adequate healthcare, mortality can be as high as 10%. In cases with complications, the rate may rise to 20–30%.[74] In 2012, the number of deaths due to measles was 78% lower than in 2000 due to increased rates of immunization among UN member states.[18]

Even in countries where vaccination has been introduced, rates may remain high. Measles is a leading cause of vaccine-preventable childhood mortality. Worldwide, the fatality rate has been significantly reduced by a vaccination campaign led by partners in the Measles Initiative: the American Red Cross, the United States CDC, the United Nations Foundation, UNICEF and the WHO. Globally, measles fell 60% from an estimated 873,000 deaths in 1999 to 345,000 in 2005.[81] Estimates for 2008 indicate deaths fell further to 164,000 globally, with 77% of the remaining measles deaths in 2008 occurring within the Southeast Asian region.[82]

Five out of six WHO regions have set goals to eliminate measles, and at the 63rd World Health Assembly in May 2010, delegates agreed on a global target of a 95% reduction in measles mortality by 2015 from the level seen in 2000, as well as to move towards eventual eradication. However, no specific global target date for eradication has yet been agreed to as of May 2010.[83][84]

Europe

In 2013–14, there were almost 10,000 cases in 30 European countries. Most cases occurred in unvaccinated individuals and over 90% of cases occurred in the five European nations: Germany, Italy, Netherlands, Romania, and United Kingdom.[18] Between October 2014 and March 2015, a measles outbreak in the German capital of Berlin resulted in at least 782 cases.[85] In 2017 numbers continued to increase in Europe to 21,315 cases, with 35 deaths.[86]

Americas

As a result of widespread vaccination, the disease was declared eliminated from the Americas in 2016.[70] It, however, occurred again in 2017 and 2018 in this region.[87]

United States

Before immunization in the United States, between three and four million cases occurred each year.[5] The United States was declared free of circulating measles in 2000, with 911 cases from 2001 to 2011. In 2014 the CDC said endemic measles, rubella, and congenital rubella syndrome had not returned to the United States.[88] Occasional measles outbreaks persist, however, because of cases imported from abroad, of which more than half are the result of unvaccinated U.S. residents who are infected abroad and infect others upon return to the United States.[88] The CDC continues to recommend measles vaccination throughout the population to prevent outbreaks like these.[89]

In 2014, an outbreak was initiated in Ohio when two unvaccinated Amish men harboring asymptomatic measles returned to the United States from missionary work in the Philippines.[90] Their return to a community with low vaccination rates led to an outbreak that rose to include a total of 383 cases across nine counties.[90] Of the 383 cases, 340 (89%) occurred in unvaccinated individuals.[90]

From January 4 to April 2, 2015, there were 159 cases of measles reported to the CDC. Of those 159 cases, 111 (70%) were determined to have come from an earlier exposure in late December 2014. This outbreak was believed to have originated from the Disneylandtheme park in California. The Disneyland outbreak was held responsible for the infection of 147 people in seven U.S. states as well as Mexico and Canada, the majority of which were either unvaccinated or had unknown vaccination status.[91] Of the cases 48% were unvaccinated and 38% were unsure of their vaccination status.[92] The initial exposure to the virus was never identified.

In 2015, a U.S. woman in Washington state died of pneumonia, as a result of measles. She was the first fatality in the US from measles since 2003.[93] The woman had been vaccinated for measles and was taking immunosuppressive drug for another condition. The drugs suppressed the woman's immunity to measles, and the woman became infected with measles; she did not develop a rash, but contracted pneumonia, which caused her death.[94]

In June 2017, the Maine Health and Environmental Testing Laboratory confirmed a case of measles in Franklin County. This instance marks the first case of measles in 20 years for the state of Maine.[95] In 2018 one case occurred in Portland, Oregon, with 500 people exposed; 40 of them lacked immunity to the virus and were being monitored by county health officials as of July 2, 2018.[96] There were 273 cases of measles reported throughout the United States in 2018,[97] including an outbreak in Brooklyn with more than 200 reported cases from October 2018 to February 2019. The outbreak was tied with population density of the Orthodox Jewish community, with the initial exposure from an unvaccinated child that caught measles while visiting Israel.[98][99]

In January and February 2019, Washington state reported an outbreak of at least 58 confirmed cases of measles, most within Clark County, which has a higher rate of vaccination exemptions compared to the rest of the state; nearly one in four kindergartners in Clark did not receive vaccinations, according to state data.[98] This led state governor Jay Inslee to declare a state of emergency, and the state's congress to introduce legislation to disallow vaccination exemption for personal or philosophical reasons.[100] The resurgence of measles in the region was caused by parents choosing not to have their children vaccinated.[101][102][103][104]

Brazil

The spread of measles had been interrupted in Brazil as of 2016, with the last known case twelve months earlier.[105] This last case was in the state of Ceará.[106]

Southeast Asia

In the Vietnamese measles epidemic in spring of 2014, an estimated 8,500 measles cases were reported as of April 19, with 114 fatalities;[109] as of May 30, 21,639 suspected measles cases had been reported, with 142 measles-related fatalities.[110]

In the Naga Self-Administered Zone in a remote northern region of Myanmar, at least 40 children died during a measles outbreak in August 2016 that was probably caused by lack of vaccination in an area of poor health infrastructure.[111][112]

History

Estimates based on modern molecular biology place the emergence of measles as a human disease sometime after 500 AD[113] (the former speculation that the Antonine Plague of 165–180 AD was caused by measles is now discounted). The first systematic description of measles, and its distinction from smallpox and chickenpox, is credited to the Persian physician Rhazes (860–932), who published The Book of Smallpox and Measles.[114] Given what is now known about the evolution of measles, Rhazes' account is remarkably timely, as recent work that examined the mutation rate of the virus indicates the measles virus emerged from rinderpest (cattle plague) as a zoonotic disease between 1100 and 1200 AD, a period that may have been preceded by limited outbreaks involving a virus not yet fully acclimated to humans.[113] This agrees with the observation that measles requires a susceptible population of >500,000 to sustain an epidemic, a situation that occurred in historic times following the growth of medieval European cities.[69]

Measles is an endemic disease, meaning it has been continually present in a community, and many people develop resistance. In populations not exposed to measles, exposure to the new disease can be devastating. In 1529, a measles outbreak in Cuba killed two-thirds of those natives who had previously survived smallpox. Two years later, measles was responsible for the deaths of half the population of Honduras, and it had ravaged Mexico, Central America, and the Inca civilization.[116]

Between roughly 1855 and 2005, measles has been estimated to have killed about 200 million people worldwide.[117] Measles killed 20 percent of Hawaii's population in the 1850s.[118] In 1875, measles killed over 40,000 Fijians, approximately one-third of the population.[119] In the 19th century, the disease killed 50% of the Andamanese population.[120] Seven to eight million children are thought to have died from measles each year before the vaccine was introduced.[18]

In 1954, the virus causing the disease was isolated from a 13-year-old boy from the United States, David Edmonston, and adapted and propagated on chickembryotissue culture.[121] To date, 21 strains of the measles virus have been identified.[122] While at Merck, Maurice Hilleman developed the first successful vaccine.[123] Licensed vaccines to prevent the disease became available in 1963.[124] An improved measles vaccine became available in 1968.[125] Measles as an endemic disease was eliminated from the United States in 2000, but continues to be reintroduced by international travelers.[126]

Society and culture

German anti-vaccination campaigner and HIV/AIDS denialist[127]Stefan Lanka posed a challenge on his website in 2011, offering a sum of €100,000 for anyone who could scientifically prove that measles is caused by a virus and determine the diameter of the virus.[128] He posits that the illness is psychosomatic and that the measles virus does not exist. When provided with overwhelming scientific evidence from various medical studies by German physician David Bardens, Lanka did not accept the findings, forcing Bardens to appeal in court. The legal case ended with the ruling that Lanka was to pay the prize.[85][129] The case received wide international coverage that prompted many to comment on it, including neurologist, well-known skeptic and science-based medicine advocate Steven Novella, who called Lanka "a crank".[130] As outbreaks easily occur in under-vaccination populations, the disease is seen as a test of sufficient vaccination within a population.[131]

Names

Other names include morbilli, rubeola, red measles, and English measles.[1][2]

Research

In May 2015, the journal Science, published a report in which researchers found that the measles infection can leave a population at increased risk for mortality from other diseases for two to three years.[132][133]

A specific drug treatment for measles, ERDRP-0519, has shown promising results in animal studies, but has not yet been tested in humans.[134][135][136]

^Schrör K (2007). "Aspirin and Reye Syndrome: A Review of the Evidence". Paediatric Drugs. 9 (3): 195–204. doi:10.2165/00148581-200709030-00008. PMID17523700. Archived from the original on 2011-06-29. Retrieved 2011-03-17. The suggestion of a defined cause-effect relationship between aspirin intake and Reye syndrome in children is not supported by sufficient facts. Clearly, no drug treatment is without side effects. Thus, a balanced view of whether treatment with a certain drug is justified in terms of the benefit/risk ratio is always necessary. Aspirin is no exception.

^Reye's Syndrome at NINDS "Epidemiologic evidence indicates that aspirin (salicylate) is the major preventable risk factor for Reye's syndrome. The mechanism by which aspirin and other salicylates trigger Reye's syndrome is not completely understood."